POLH Gene – DNA Polymerase Eta: Function, Mutations & Disease

POLH encodes DNA polymerase eta (Pol η), a Y-family DNA polymerase specialized in translesion synthesis (TLS). Pol η accurately bypasses UV-induced cyclobutane pyrimidine dimers (CPDs) by inserting two adenines opposite the dimer, preventing replication fork stalling and genomic instability. It also participates in somatic hypermutation of immunoglobulin genes. Loss-of-function mutations in POLH cause xeroderma pigmentosum variant (XP-V), characterized by extreme UV sensitivity, high freckling, and a >1000-fold increased risk of skin cancer.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Translesion synthesis (Reactome R-HSA-5655862)

• DNA damage bypass (KEGG hsa03440)

• Nucleotide excision repair (KEGG hsa03420)

DNA polymerase eta (Pol η) is a 713-amino acid Y-family polymerase with a unique ability to replicate past UV-induced cyclobutane pyrimidine dimers with high accuracy. It contains an N-terminal polymerase domain and a C-terminal PCNA-interacting motif (PIP box). Pol η is recruited to stalled replication forks via monoubiquitinated PCNA, enabling TLS. Defects in Pol η cause xeroderma pigmentosum variant (XP-V), a disorder marked by UV hypersensitivity and predisposition to skin cancers. Pol η also contributes to somatic hypermutation in B cells by introducing mutations at A/T bases.